Many cardiovascular diseases are caused by the hyperactivity of the autonomic nervous system (ANS), including such disorders as cardiac arrhythmias including (but not limited to) atrial and ventricular fibrillation and tachycardia, vasovagal syncope, inappropriate sinus tachycardia, and hypertension. Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring treatment and frequently progresses from paroxysmal AF to permanent AF. AF accounts for nearly 20% of the strokes in the U.S. AF inflicted approximately 2.3 million Americans in 2004 and costs the health care system nearly $12 billion a year to treat AF and AF-related strokes. By the year 2050, the number of AF patients is projected to increase to 16 million as the population ages. Nearly half of AF patients are refractory (i.e., do not respond) to anti-arrhythmic drugs and require non-pharmacologic treatment, i.e., surgical or catheter ablation. Clinical trials aimed at ablative treatment of AF resulted in a <50% success rate after five years of follow-up. Standard catheter or surgical ablation procedures produce lesion sets to isolate the pulmonary vein (PV)-atrial junction, containing the presumed triggers and/or substrate for AF. However, in a single procedure, PV antrum isolation only leads to less than 50% success at 5 years for the earliest stage of AF (paroxysmal AF) and approximately 30% for more persistent forms of AF. This approach, widely practiced worldwide, has many drawbacks including a relatively low success rate and various complications, including PV stenosis, cardiac tamponade, esophageal injury, and minor or major strokes. Despite all the advances in ablation technologies in the past 12 years, success of AF ablation has not improved. The unsatisfactory efficacy of AF ablation is mainly due to insufficient understanding of the electrophysiological mechanism(s) underlying the initiation of AF and its progression into more persistent forms of AF. A mechanistically-based therapy is still lacking.
Prior studies of AF initiation in patients and animals indicate that (unbalanced) activation of both sympathetic and parasympathetic nervous systems often precede AF onset. Mammalian hearts are dually innervated by the extrinsic and intrinsic cardiac autonomic nervous system (CANS). It is known that the intrinsic CANS is a neural network composed of many ganglionated plexi and interconnecting nerves and/or neurons. In this neural network, bilateral autonomic inputs come together at many “integration centers” before giving rise to final common pathways that control cardiac rhythm and force of contraction. These intrinsic integration centers are located in epicardial ganglionated plexi (GP) or ligament of Marshall which are overlain by epicardial fat pads. In mammalian hearts, the ligament of Marshall and four major atrial GP (anterior right GP, ARGP; inferior right GP, IRGP; superior left GP, SLGP; and inferior left GP, ILGP) are located adjacent to the junction of the atrium and four pulmonary veins. Stellate ganglia, the gateway of sympathetic innervation to the heart, are located just above the apex of the lung. In previous studies, the inventors have shown that electrical stimulation or injection of acetylcholine into the GP near the PV-atrial junction can initiate sustained AF arising from the PV-atrial junction. Ablation of the four major atrial GP and ligament of Marshall markedly suppressed the inducibility and maintenance of AF in multiple animal models, including the rapid atrial pacing model. Notably, the lesion sets of a standard RF ablation (PV antrum isolation) involve ablation of three of the four major atrial GP, the ligament of Marshall, and numerous autonomic nerves, indicating that autonomic denervation is a major contributor to the antiarrhythmic effects of AF ablation. Importantly, ablations involving only the major atrial GP, without PV antrum isolation, yielded similar results to the standard PV antrum isolation but produced significantly less collateral damage to the atrial myocardium and possibly less consequent iatrogenic left atrial flutter. While re-innervation may occur 3-6 months after RF catheter ablation procedures, the clinical benefits of GP ablation lasted 16-18 months, suggesting that permanent injury to the autonomic neurons in intrinsic CANS may underlie the therapeutic effects of ablation, because unlike nerves, neurons seldom regenerate.
Targeted drug delivery is an increasingly used nanomedicine technology in which delivery of therapeutics to target tissues may increase drug efficacy, eliminate side effects, and reduce costs. Polymeric nanoparticles whose diameters can range from 10-300 nanometers can be formulated as nanocomposites with encapsulated drugs for burst and controlled release. Superparamagnetic nanoparticles, approved in the early 1990s for clinical magnetic resonance imaging enhancement, can be encapsulated in polymers, silicon, or carbohydrates and pulled into tissues to produce more precise lesion sets, thereby reducing non-specific damages.
Standard ablation procedures require the creation of two circumferential lesions to isolate the antrum of all the PVs. Currently, atrial ablation strategies focus on isolating and/or destroying atrial tissue that presumably is responsible for AF, although the long-term consequences of extensive damage to the atrial myocardium, neural elements, and atrial contractility are yet to be discovered.
Multiple basic science studies have demonstrated a significant impact on AF after the major left atrial GPs were ablated. Using a rapid atrial pacing model, Lu et al. (Cardiovas. Res., 84:245-52 (2009); the entire contents of which are hereby expressly incorporated herein by reference) showed that shortening of the effective refractory period (ERP) and an increase of ERP dispersion, as well as increased AF inducibility caused by rapid atrial pacing for 3 hours, were all reversed by ablation of the 4 major atrial GP and the ligament of Marshall (LOM). In animals receiving GP ablation first, rapid atrial pacing for 6 hours failed to change the ERP, ERP dispersion, and AF inducibility. Other animal studies also demonstrated that after ablation of the GP and LOM, AF became more difficult to initiate and sustain. AF often terminated after GP ablation. The inventors proposed that autonomic denervation may serve as a therapeutic modality to prevent paroxysmal AF to progress to more persistent forms of AF. Several clinical studies have indicated the benefits of autonomic denervation by targeting the major atrial GPs identified by high frequency stimulation. When GP ablation was combined with PV isolation, the success rate is significantly better than PV isolation alone. A series of recent manuscripts (Katritsis et al., Journal of American College of Cardiology, 62(24):2318-2325 (2013); Pokushalov et al., Heart Rhythm, 6:1257-64 (2009); and Pokushalov et al., Europace, 12:342-346 (2010); the entire contents of each of which are hereby expressly incorporated herein by reference) also reported similar success rates in AF ablation targeting only the major atrial GPs, in comparison to the standard PV isolation approach.
As noted, clinical studies demonstrated that GP ablation as an adjunct therapy to PV isolation improved the outcome of AF ablation, whereas GP ablation alone produced a success rate similar to the standard PV isolation. This denervation-only ablation strategy has the advantage of producing more focused lesion sets and potentially carrying a smaller risk of producing iatrogenic macro-reentrant left atrial tachycardia.
A method of direct (targeted) treatment of specific portions of the ANS for the inhibition of various disorders, such as (but not limited to) cardiovascular disorders involving the ANS, particularly for permanent inhibition of those portions of the ANS, would be highly desirable.